The present invention is for novel benzothiophene, benzofuran and indole thiazepinones, oxazepinones and diazepinones and pharmaceutically acceptable salts thereof, used to prevent the adhesion of leukocytes to endothelial cells. Leukocyte adherence to vascular endothelium is integral to the pathogenesis of inflammation. The adhesion process precedes transendothelial migration of leukocytes into surrounding tissue and ensuing tissue damage. Compounds that can block this initial adhesive interaction are expected to have efficacy in the treatment of inflammatory diseases such as rheumatoid arthritis, osteoarthritis, asthma, and psoriasis. Other indications would include but are not limited to adult respiratory distress syndrome, reperfusion injury, ischemia, ulcerative colitis, vasculitides, atherosclerosis, inflammatory bowel disease and tumor metastases.
Adhesion receptors are organized into three main families: the selectins, the immunoglobulin superfamily, and the integrins (Nature, 346:426 (1990)). Members of all three classes are involved in mediating leukocyte adhesion during inflammation (for reviews of this area see: Thrombosis and Hemostasis, 65 (3); 223 (1991), Clinical and Experimental Allergy, 20:619 (1990), Transplantation, 48:727 (1989), Biochemical Pharm., 40 (8): 1683 (1990)) . Endothelial leukocyte adhesion molecule-1 (ELAM-1 or E-selectin) is a member of the selectin family of glycoproteins that promote cell-cell adhesion. E-selectin is reported to be maximally expressed on the surface of endothelial cells 4 hours after stimulation of the endothelial cells with cytokines, such as interleukin-1 (IL-1) or tumor necrosis factor .alpha. (TNF-.alpha.) or other inflammatory mediators, such as lipopolysaccharide (LPS) (Pro. Nat. Acad. Sci., 84:9238 (1987).
Intercellular adhesion molecule-1 (ICAM-1) is a member of the immunoglobulin superfamily. It is also upregulated with maximum expression occurring 12-24 hours after stimulus. It has been shown that hours after the endothelial cells are stimulated with an inflammatory mediator both E-selectin and ICAM-1 are present on the cell surface (J. Clin. Invest., 82:1746 (1988) and J. Immun., 137:1893 (1986), Blood, 78:2721 (1991)).
The benzothiophene, benzofuran and indole thiazepinones, oxazepinones and diazepinones of the present invention have been shown to inhibit the adhesion of neutrophils to human umbilical vein endothelial cells (HUVECS) stimulated with TNF.alpha. in an in vitro assay.
The present invention also relates to the novel thiazepinones, oxazepinones and diazepinones for treating humans infected with human immunodeficiency virus (HIV) by inhibiting-the activation of HIV, latent in infected humans.
The pathogenesis of the human immunodeficiency virus (HIV) is complicated and as of yet not completely understood. The virus life cycle has theoretically been divided into afferent and efferent components. Virus binding, fusion, reverse transcription, and finally integration are among those events which encompass the afferent component of the life cycle. It is the afferent components of the HIV life cycle which is responsible for primary infection of HIV in an individual, generally followed by a burst of viraemia with or without clinical symptoms.
Many therapeutic strategies have been developed and targeted for intervention during the afferent events. See for example, Mitsuya H, Broder S, "Inhibition of the In Vitro Infectivity and Cytopathic Effect on Human T-lymphotropic Virus Type III/lymph-adenopathy Virus-associated Virus (HTLV-III/LAV) by 2',3'-Dideoxynucleosides," Proc. Natl. Acad. Sci. (USA), 83:1911-1915 (1986).
Whereas different stages of the afferent component offer the potential for effective therapeutic intervention, it has become increasingly apparent that intervention solely at these points is insufficient. After becoming infected with HIV and the disease progresses through the afferent stages, an individual experiences a prolonged period of clinical latency which may extend for several years and the individual remains in good health. At this point in time, low to absent levels of viraemia and virus replication in peripheral blood cells are achieved. At a later point, however, the disease eventually progresses to life-threatening immunosuppression (AIDS) for which there remains no cure. These later events are the clinical manifestations of the efferent stages of HIV infection.
The efferent component of the HIV life cycle includes those events necessary for the HIV provirus to successfully transcribe, translate, assemble, and produce virions. Onset of the events necessary for HIV-infected cells to progress from an asymptomatic, non-HIV expressive stage to a symptomatic, HIV expressive stage is referred to as activation. Presently, the efferent component and the cellular basis for activation is not completely understood. Nevertheless, if novel therapeutic agents and strategies are developed and implemented during the clinically asymptomatic phase to fight the progression toward AIDS, some hope may be afforded the estimated one million infected, but clinically latent, individuals.